Project 3: The goal of this project is to utilize advanced proteomics expertise and capabilities provided in the Center to conduct a set of pilot, exploratory, studies aimed at determining immunomodulatory alterations related to a series of conditions associated with opioid addiction and HIV disease. We plan to study changes resulting from opioid abuse and its pharmacological treatment, HIV pathogenesis, antiretroviral (ARV) treatment, and the potential impact of drug interactions. This project will entail obtaining blood and (in conjunction with Project 1) and CSF at specified times in 4 samples: heroin addicted and participants in a buprenorphineantiretroviral drug interaction study (RO1 DA 13004 (EMK)), a matched health control sample, a sample of heroin-addicted individuals seeking methadone maintenance treatment and a sample of heroin-addicted individuals with HIV disease seeking methadone maintenance treatment. Proteomics from samples collected at specified tfmepoints in these samples will help us to explore several questions of importance. We will explore the effect of opiate addiction on immune function and inflammation, as well as the effect of opioid pharmacotherapies in current clinical use (methadone and buprenorphine) on immune function. We will also study the question of how single ARV medications administered alone or with buprenorphine affect immune function. The study design will allow us to examine whether there are differences in immune function and inflammatory responses in patients with HIV/AIDS who are treated with highly active antiretroviral therapy (HAART) and who are methadone-maintained relative to their immune function while treated with methadone, but prior to initiation of HAART. Finally, the study design will allow us to examine the effect of medical withdrawal of opioids, either buprenorphine or methadone, on immune function and inflammatory responses. Findings from these studies will offer some of the first insights into cellular mechanisms of how abuse of heroin, treatment with opioids that may alter immune response(s), the effect of ARV, and the potential of drug interactions between opioids and ARV alter immune responses.